IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses.

Abstract

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.

• Authors: Shuai Shao, Lam C Tsoi, William R Swindell, Jiaoling Chen, Ranjitha Uppala, Allison C Billi, Xianying Xing, Chang Zeng, Mrinal K Sarkar, Rachael Wasikowski, Yanyun Jiang, Joseph Kirma, Jingru Sun, Olesya Plazyo, Gang Wang, Paul W Harms, John J Voorhees, Nicole L Ward, Feiyang Ma, Matteo Pellegrini, Alexander Merleev, Bethany E Perez White, Robert L Modlin, Bogi Andersen, Emanual Maverakis, Stephan Weidinger, J Michelle Kahlenberg, Johann E Gudjonsson
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 10 Pg. 2436-2448 (10 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 33864770 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• NF-kappa B
• Transcription Factors
• Tumor Suppressor Proteins
• ZNF750 protein, human
• Interleukin-1 Receptor-Associated Kinases

Topics

• Cell Differentiation
• Cells, Cultured
• Dermatitis, Atopic (etiology)
• Epidermis (pathology)
• Humans
• Inflammation (etiology)
• Interleukin-1 Receptor-Associated Kinases (physiology)
• NF-kappa B (physiology)
• Psoriasis (etiology)
• Severity of Illness Index
• Signal Transduction
• Transcription Factors (physiology)
• Tumor Suppressor Proteins (physiology)